Genomics-guided therapy for early breast cancer after initial treatment

Genomics Guided Targeted Post-neoadjuvant Therapy in Patients With Early Breast Cancer - a Multicenter, Open-label, Umbrella Phase-II Study - COGNITION-GUIDE

This study is testing if personalized treatment plans based on genetic information can help people with early-stage breast cancer who didn't fully respond to initial therapy avoid relapse.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 240 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: German Cancer Research Center (other)
• Drugs / interventions: Atezolizumab, Sacituzumab, Trastuzumab, Pertuzumab, chemotherapy
• Locations: 9 sites (Heidelberg, Baden-Wurttemberg and 8 other locations)
• Trial ID: NCT05332561 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to improve outcomes for patients with early-stage breast cancer who have not achieved a complete pathological response after neoadjuvant therapy. It involves a seven-arm phase II trial that implements individualized genomic-guided post-neoadjuvant therapies to reduce the risk of relapse in high-risk patients. By utilizing advanced genomic sequencing techniques, the study seeks to tailor treatment based on the specific molecular characteristics of the cancer, potentially enhancing the effectiveness of therapy. The trial is designed to provide targeted interventions at a stage when the tumor burden is low, which may lead to better long-term outcomes.

Who should consider this trial

Good fit: Ideal candidates include adults with non-metastatic early-stage breast cancer who have undergone neoadjuvant chemotherapy and have residual disease.

Not a fit: Patients with metastatic breast cancer or those who have not undergone prior neoadjuvant therapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could significantly lower the risk of cancer recurrence in high-risk early breast cancer patients.

How similar studies have performed: Previous studies have shown promise in using genomic-guided therapies in advanced cancer stages, but this approach in early-stage breast cancer is relatively novel.

Eligibility criteria

Inclusion Criteria:

1. Provision of written informed consent
2. Female and male patients with non-metastatic early (stage I-III) breast cancer aged ≥ 18 years
3. Conducted neoadjuvant chemotherapy and surgery as well as conducted standard post-neoadjuvant treatment +/- radiotherapy (standard according to German guidelines except Abemaciclib and Olaparib)
4. For patients with initially triple negative (TNBC) or HER2-positive breast cancer:

   • Non-pCR defined as other than ypT0/is ypN0
5. For patients with initially hormone receptor positive and HER2-negative breast cancer: Non-pCR and CPS-EG score

   * ≥ 3 and ypN0, or
   * ≥ 2 and ypN+
6. ECOG Performance Status ≤ 1
7. Acute effects of any prior therapy resolved to baseline severity or National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) Grade ≤ 1 except for adverse effects not constituting a safety risk by investigator judgement
8. Postmenopausal or evidence of non-childbearing status. For women of childbearing potential negative urine pregnancy test at post-operative screening and baseline as well as highly effective forms of contraception have to be in place thereafter

   * Evidence of childbearing potential is defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile
   * Postmenopausal or evidence of non-childbearing status is defined as:

     * Amenorrhea for 1 year or more without an alternative medical cause following cessation of exogenous hormonal treatments plus follicle stimulating hormone (FSH) levels in the postmenopausal range in women not using hormonal contraception or hormonal replacement therapy
     * Chemotherapy-induced menopause
     * Surgical sterilisation (bilateral oophorectomy, bilateral salpingectomy, total hysterectomy or tubal ligation at least 6 weeks before IMP treatment)
     * Female patients with age ≥ 60 years
   * A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy
9. Female patients of childbearing potential and male patients with partners of childbearing potential who are sexually active must agree to the use of two forms of contraception in combination (male condom and one highly effective method). These should be started immediately after signing the informed consent form and continued throughout the period of study treatment plus a substance-depending time period (see respective sub-protocol) for female patients and a substance-depending time period for male patients. Details on contraception and pregnancy testing for male and female patients (and if indicated their partners) under IMP treatment are described within the respective sub-protocol
10. Ability of patient to understand and comply with the protocol for the duration of the study, including treatment and scheduled visits and examinations
11. Adequate bone marrow, renal, and hepatic function defined by laboratory tests\*

The biomarker-guided eligibility for the respective study arm is evaluated and determined exclusively by the NCT molecular tumor board on the basis of results of the COGNITION molecular diagnostic registry platform. Biomarkers that allow inclusion in the respective arm are:

* Arm 1 (Atezolizumab, Immune Evasion ): PD-L1 positivity measure by IHC (≥1% on immune cells within the tumor), MSI-high status (validated by PCR), TMB-H (≥10mut/MB), CD274 amplification
* Arm 2 (Inavolisib, PI3K): Known/reported oncogenic mutation in PIK3Ca
* Arm 3 (Ipatasertib, AKT): Aberrations predicting increased PI3K-AKT pathway activity except PI3K-mutations, HR positive histology
* Arm 4 (Olaparib, PARP, DNA-Repair): Inactivating somatic or germline BRCA1/2 mutation including homozygous deletions, Inactivating germline PALB2 mutations
* Arm 5 (Sacituzumab Govitecan, TROP-2): Trop-2-overexpression (with IHC and except known/reported homozygous polymorphism in UGT1A1\*28)
* Arm 6 (Trastuzumab / Pertuzumab, ERBBB): HER2 exon-20 insertion, Activating HER2-mutation

Exclusion Criteria:

1. Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1 grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥ 5 year
2. Concurrent severe, uncontrolled systemic disease that would place patient at undue risk or interfere with planned treatment
3. Concurrent participation or previous treatment within 30 days in another interventional clinical trial
4. Persistent toxicity (≥ Grade 2 according to NCI CTCAE v5.0 caused by previous cancer therapy, excluding alopecia
5. Clinical signs of active infection (\> Grade 2 according NCI CTCAE v5.0)
6. History of or newly diagnosed human immunodeficiency virus (HIV) infection and immunocompromised patients
7. Active Hepatitis A virus infection
8. Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface antigen (HBsAg) test. Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for the study if active HBV infection is ruled out on the basis of HBV DNA viral load per local guidelines
9. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at screening confirmed by a polymerase chain reaction (PCR) positive for HCV RNA
10. Dementia or significant impairment of cognitive state
11. Epilepsy requiring pharmacologic treatment
12. Pregnancy and breast feeding
13. Inability to take oral medication and gastrointestinal disorders likely to interfere with absorption of study medication
14. Major surgery (any invasive operative procedure in which a more extensive resection is performed, e.g. a body cavity is entered, organs are removed, or normal anatomy is altered) within four weeks before screening and baseline excluding breast-tumor resection after neoadjuvant chemotherapy. Patients must have recovered from any effects of any major surgery
15. Systemic chemotherapy or radiotherapy within four weeks or a longer period depending on the characteristics of the agents used
16. Heart failure classified as New York Heart Association (NYHA) II/III/IV
17. Severe obstructive or restrictive ventilation disorder
18. Patients with clinically active tuberculosis
19. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug
20. Is taking or requiring the continued use of any of the prohibited concomitant medications listed in the respective subprotocols at baseline
21. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder or non-malignant systemic disease. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord compression or, superior vena cava syndrome.

Where this trial is running

Heidelberg, Baden-Wurttemberg and 8 other locations

• National Center for Tumor Diseases — Heidelberg, Baden-Wurttemberg, Germany (RECRUITING)
• Universitätsklinikum Tübingen — Tübingen, Baden-Wurttemberg, Germany (RECRUITING)
• Universitätsklinikum Augsburg — Augsburg, Bavaria, Germany (RECRUITING)
• Universitätsklinikum Erlangen — Erlangen, Bavaria, Germany (RECRUITING)
• Universitätsklinikum Ulm — Ulm, Bavaria, Germany (RECRUITING)
• Universitätsklinikum Würzburg — Würzburg, Bavaria, Germany (NOT_YET_RECRUITING)
• Universitätsklinikum Carl-Gustav-Carus — Dresden, Saxony, Germany (RECRUITING)
• Charité - Universitätsmedizin Berlin — Berlin, Germany (RECRUITING)
• Universitätsklinikum Essen — Essen, Germany (NOT_YET_RECRUITING)

Study contacts

• Principal investigator: Andreas Schneeweiss, Prof. Dr. — National Center for Tumor Diseases (NCT)
• Study coordinator: Andreas Schneeweiss, Prof. Dr.

Conditions: Early-stage Breast Cancer, Breast Cancer, Post-neoadjuvant therapy, genomics-guided, molecular diagnostic, targeted therapy, high risk